刘红
中国医学科学院阜外医院 卫生部心血管药物临床研究重点实验室
Nifekalant hydrochloride is a class III antiarrhythmic agent which could increase the duration of the action potential and the effective refractory period of ventricular and atrial myocytes by blocking the K+ current. Nifekalant is used to prevent ventricular tachycardia/ventricular fibrillation. QT interval prolongation is the main measurable drug effect. However, due to the complicated dosing plan in clinic, the relationship among dosage, time, drug concentration and efficacy is not fully understood. In this study, a single-center, randomized, blind, dose-ascending, placebo-controlled study was conducted to explore the intrinsic characteristics of nifekalant injection in healthy Chinese volunteers by a population pharmacokinetic (PK)-pharmacodynamic (PD) model approach. 42 subjects were enrolled in this study and received one of three dose plans (loading dose on Day 1 (0.15, 0.3 or 0.5 mg/kg), loading dose followed by maintenance dose (0.2, 0.4 or 0.8 mg/kg/h) on Day 4) or vehicle. Blood samples were drawn for PK evaluation, and ECGs were recorded for QTc calculation at the designed timepoints. No Torsades de Pointes occurred during the study. The popPK model of nifekalant injection could be described by a two-compartment model with first-order elimination. The population mean clearance (CL) was 53.8 L/h. The population mean distribution volume of the central (Vc) and peripheral (Vp) compartments was 8.27 L and 45.6 L, respectively. A nonlinear dose-response (Emax) model well described the pharmacodynamic effect (QTc interval prolongation) of nifekalant. The Emax and EC50 from current study were 101 ms and 342 ng/mL, respectively.
Journal of pharmacokinetics and pharmacodynamics 2024
Mitochondrial toxicity induced by therapeutic drugs is a major contributor for cardiotoxicity, posing a serious threat to pharmaceutical industries and patients' lives. However, mitochondrial toxicity testing is not incorporated into routine cardiac safety screening procedures. To accurately model native human cardiomyocytes, we comprehensively evaluated mitochondrial responses of adult human primary cardiomyocytes (hPCMs) to a nucleoside analog, remdesivir (RDV). Comparison of their response to human pluripotent stem cell-derived cardiomyocytes revealed that the latter utilized a mitophagy-based mitochondrial recovery response that was absent in hPCMs. Accordingly, action potential duration was elongated in hPCMs, reflecting clinical incidences of RDV-induced QT prolongation. In a screen for mitochondrial protectants, we identified mitochondrial ROS as a primary mediator of RDV-induced cardiotoxicity. Our study demonstrates the utility of hPCMs in the detection of clinically relevant cardiac toxicities, and offers a framework for hPCM-based high-throughput screening of cardioprotective agents.
Science China. Life sciences 2024
Hepatotoxicity with low-molecular-weight heparin (LMWH) or fondaparinux is a relatively common adverse reaction. This study assessed the effects of LMWH and fondaparinux on liver function in patients with pulmonary embolism based on a retrospective cohort. As a result, a total of 463 patients with pulmonary embolism and treated with LMWH (enoxaparin sodium or nadroparin calcium) or fondaparinux sodium were included. Liver dysfunction was identified in 79 patients (17.1%), of whom 97.5% had grade 1 drug-induced liver injury (DILI) and 2.5% had grade 2 DILI. The results showed that liver dysfunction usually occurred in the first week after anticoagulant administration, and the liver tests of all patients with liver dysfunction gradually recovered or alleviated at discharge. The multivariable logistic regression analysis indicated that a longer treatment course and hepatitis B surface antigen-positive (HBsAg+) were risk factors for liver dysfunction (P < .05). Moreover, nadroparin calcium had the highest risk of liver dysfunction, approximately 2.2 times (95% confidence interval [CI], 1.1740-4.224; P = .015) that of enoxaparin sodium. In conclusion, nearly one-fifth and 10% of patients prescribed with LMWH or fondaparinux, respectively, for pulmonary embolism had liver dysfunction, mainly with mild liver injury and characterized by self-limited elevated serum transaminase levels. Hence, during the 3 anticoagulant applications, we should pay more attention to the monitoring of liver function in the first week and transit to oral anticoagulants if possible, especially for patients who are HBsAg+ or suffering from other liver diseases.
Journal of clinical pharmacology 2020
BACKGROUND:Organ dysfunction caused by hypothermic circulatory arrest continues to concern surgeons. The aortic balloon occlusion (ABO) technique can significantly shorten the circulatory arrest time in total arch replacement with frozen elephant trunk (TAR with FET). This study aims to analyze the renal protective effect of the ABO technique and to analyze the predictors of acute kidney injury (AKI) and continuous renal replacement therapy (CRRT) after TAR with FET.METHODS:Between August 2017 and September 2018, 247 patients who underwent TAR with FET were divided into ABO and moderate hypothermic circulatory arrest (MHCA) groups. The primary endpoint was postoperative AKI defined by the Kidney Disease Improving Global Outcomes (KDIGO) criteria. Multivariable logistic analysis was used to identify the predictors of AKI and CRRT after TAR with FET.RESULTS:With the application of the ABO technique, the circulatory arrest time was significantly shortened (ABO 4, IQR: 3-6 vs. MHCA 18, IQR: 16-20, P<0.001). Meanwhile, surgeons safely set the lowest nasopharyngeal temperature at a higher grade (ABO 28.1, IQR: 27.4-28.5 vs. MHCA 24.7, IQR: 24.1-25.1, P<0.001). The peak serum creatinine (SCr) values within 48 hours after the surgery was lower in the ABO group than in the MHCA group (ABO 124, IQR: 97-173 vs. MHCA 146, IQR: 108-221, P=0.008). The distribution of AKI grade according to the KDIGO criteria differed between the two groups (P=0.04): more patients in the ABO group were free from AKI (Grade 0) than patients in the MHCA group (33% vs. 23.1%), and the proportion of patients with high-grade AKI (Grades 2 and 3) in the ABO group was lower than that in the MHCA group (21% vs. 32%). The ABO technique was associated with reduced potential for AKI, but was not protective for CRRT.CONCLUSIONS:The ABO technique significantly shortened the circulatory arrest time and safely elevated temperature, and provided better renal protection in patients undergoing TAR with FET. The ABO technique did not reverse the need for CRRT, nor did it reduce mortality or major adverse events.
Annals of cardiothoracic surgery 2020
BACKGROUND:Early mortality and cerebral injury are severe complications of aortic arch surgery, but data from Asian countries are scarce. We reviewed the results of patients who underwent aortic arch replacement with deep hypothermic circulatory arrest (DHCA) and antegrade selective cerebral perfusion (ASCP) at our institution to analyse pre- and intraoperative predictors of early death and neurological complications.METHODS:Clinical data of adult patients who underwent aortic arch surgery with DHCA plus ASCP between January 2005 and December 2011 were retrospectively analysed. Univariate and multivariate analyses were performed to identify predictors of adverse outcome defined as 30-day mortality and permanent neurological dysfunction (PND), and transient neurological dysfunction (TND).RESULTS:A total of 626 patients were included in the study. The average age of the patients was 45.0±10.7 years with male predominance (77.0%). The incidence of adverse outcome was 5.8%, consisting of 4.6% 30-day mortality and 1.9% PND. Transient neurological dysfunction was found in 13.9% patients. Multiple logistic regression showed that stroke (OR=7.846, 95% CI: 2.737-22.489, p<0.001), emergency (OR=2.198, 95% CI: 1.019-4.740, p=0.045), CPB time (OR=1.009, 95% CI: 1.004-1.014, p<0.001), CABG (OR=2.613, 95% CI: 1.066-6.405, p=0.036) and packed red blood cells (OR=1.113, 95% CI: 1.038-1.193, p=0.003) were independent predictors of adverse outcome, and acute type A aortic dissection (OR=2.635, 95% CI: 1.535-4.524, p<0.001), preoperative neurological deficits (OR=5.326, 95% CI: 1.529-18.548, p=0.009), CPB time (OR=1.004, 95% CI: 1.000-1.007, p=0.026) and cerebral low-flow time (OR=1.034, 95% CI: 1.003-1.066, p=0.033) were associated with TND.CONCLUSIONS:A history of stroke was a strong predictor of adverse outcome, and acute type A aortic dissection and preoperative neurological deficits had a high correlation with TND. The predictors identified in this study may help clinicians to optimise the risk evaluation and perioperative clinical management of patients undergoing aortic arch surgery to reduce morbidity and mortality.
Heart, lung & circulation 2017
BACKGROUND:Apolipoprotein CIII (apoCIII) is considered to impair the anti-atherogenic effect of high density lipoprotein (HDL) in coronary heart disease (CHD) patients, and apoCIII content in HDL (HDL-apoCIII) predicts CHD more accurately. However, the relationship between HDL-apoCIII and CHD, and the effect of statin treatment on HDL-apoCIII are still unclear. The aims of the study are to establish the association of HDL-apoCIII with CHD, and investigate the effect of statin treatment on HDL-apoCIII in CHD patients.METHODS:We conducted a hospital-based observational study. Totally 80 non-CHD patients and 120 CHD patients without statin treatment were previously enrolled in this study. All the CHD patients received statin treatment, and 63 of them were followed after 3 months of regular statin treatment. HDL sample of each patient was isolated by density gradient ultracentrifugation from fasting venous plasma, and HDL-apoCIII of each patient was measured by ELISA method.RESULTS:HDL-apoCIII was significantly higher in CHD patients than non-CHD patients (p < 0.05), and it was still an independent predictor of CHD after adjusting for other factors. Total plasma apoCIII, especially HDL-apoCIII was significantly elevated after statin treatment in CHD patients, whereas total cholesterol (TC), low density lipoprotein cholesterol (LDL-c) and apolipoprotein B (apoB) were decreased significantly (p < 0.05). Compared with CHD patients without diabetes mellitus (DM), the effect of statin treatment on apoCIII markers was minor in CHD patients with DM. And HDL-apoCIII correlated with plasma TG significantly in non-CHD and CHD patients (p < 0.05), but the correlation in CHD patients did not exist after statin treatment (p > 0.05).CONCLUSIONS:HDL-apoCIII has a significant and positive association with CHD. Although conventional atherogenic lipid markers have a significantly decrease in CHD patients after statin treatment, HDL-apoCIII has a further elevation at the same time.
Lipids in health and disease 2015
OBJECTIVES:This study aims to compare the protein composition of high-density lipoprotein (HDL) particles in coronary heart disease (CHD) patients and controls by proteomic methods.BACKGROUND:HDL has been reported to exert pro-atherogenic properties in CHD patients. Accumulating evidence indicates that HDL composition, rather than the HDL-C level, determines its functions. The changes in HDL composition involved in the conversion of anti-atherogenic to pro-atherogenic properties in CHD patients are currently unknown.METHODS AND RESULTS:iTRAQ combined with nanoLC-MS/MS was performed to obtain a differential expression profile of the HDL pooled samples of the male age-matched CHD patients and controls (n = 10/group). Of the 196 proteins identified in the examined HDL, 12 were differentially expressed between the CHD patients and the controls, including five up-regulated proteins and seven down-regulated proteins. Using GO analysis, we determined that the up-regulated proteins were mostly involved in inflammatory reactions, displaying a potential pro-atherogenic profile. In contrast, the down-regulated proteins were mostly involved in lipid metabolism processes, displaying anti-atherogenic properties. To confirm the proteomic results, serum amyloid A (SAA) and apoC-I were selected and quantified by ELISA, in the same population as the proteomic analysis, as well as another independent population (n = 120/group). Consistent with the proteomic results, the amount of SAA was significantly increased, and apoC-I was significantly decreased in the HDL particles of CHD patients compared with those of controls (P<0.05).CONCLUSIONS:Our study shows that the HDL proteome changes to a pro-atherogenic profile in CHD patients, which might compromise the protective effects of HDL. Proteomic analysis of HDL composition may provide more relevant information regarding their functional properties than steady-state HDL-C levels.
PloS one 2014
BACKGROUND:Whether two clopidogrel pretreatment strategies prior to elective percutaneous coronary intervention (PCI): a 300 mg loading dose (LD) in clopidogrel naїve patients and a 75 mg maintenance dose (MD) once daily in patients on chronic clopidogrel therapy play the same role in the platelet inhibition in Chinese with different CYP2C19 genotypes remains unknown. We aim to evaluate the impact on platelet inhibition by clopidogrel pretreatment strategy and its interaction effect with CYP2C19 genotype.METHODS:Chinese patients undergoing PCI (n = 840) were assigned to 2×2 groups in the trial according to different clopidogrel pretreatment strategies (470 patients in LD, 370 patients in MD) and CYP2C19 genotypes (494 carriers of any CYP2C19 *2 or *3 loss-of-function allele, 346 non-carriers). The primary outcome was platelet aggregation (PA) as measured by the 10 µmol/L adenosine diphosphate induced light transmission aggregation.RESULTS:Compared with MD group, LD strategy showed a significantly higher PA-((59.22 ± 11.67)% vs. (52.83 ± 12.17)%, P < 0.01), similar PA difference was observed in CYP2C19 loss-of-function carriers compared with non-carriers ((59.41 ± 10.91)% vs. (52.10 ± 12.90)%, P < 0.01). LD patients in either the CYP2C19 loss-of-function allele carrier or non-carrier group showed a significantly higher PA compared with MD group ((61.50 ± 10.61)% vs. (56.84 ± 10.74)%, P < 0.01; (56.06 ± 12.34)% vs. (46.88 ± 11.78)%, P < 0.01, respectively). A quantitative interaction effect was observed between clopidogrel pretreatment strategy and CYP2C19 genotype (P = 0.001).CONCLUSION:The 300 mg LD strategy results in a decreased effect on platelet inhibition compared with the 75 mg MD in Chinese patients receiving clopidogrel prior to PCI, especially in the CYP2C19 2 or 3 loss-of-function allele non-carriers. (ClinicalTrials.gov number NCT01710436)
Chinese medical journal 2014
OBJECTIVE:To search new clues to reveal the action mechanism of inhaled anesthetics.METHODS:Three kinds of Drosophila melanogaster were used as studied models: the wild type strain (H), the sevoflurane-sensitive strain (S), and the sevoflurane-resistant strain (R). Differential display reverse transcriptional-polymerase chain reaction method was performed to examine the differentially expressed fragments between Drosophila induced with and without sevoflurane. Rapid amplification of cDNA ends (RACE) method was used to clone the full length cDNA from positive differentially expressed fragments.RESULTS:Thirty-one differentially expressed fragments were found between the two groups. Three fragments were identified as the positive differentially expressed fragments by Northern blot analysis. Two full-length cDNAs were cloned by RACE method, among which one was a 1.0 kb Drosophila calmodulin (CaM), located on Chr.2; the other was a 4.1 kb gene with unknown function (No.45), located on Chr.3.CONCLUSION:The two full-length cDNAs belong to the genes that related to anesthetic action pathway, which might participate in the regulation of cellular functions and signal transduction pathways. The two genes that we found should provide a novel way to study the mechanism of inhaled anesthetic action.
Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae 2004
OBJECTIVE:Previous studies have shown that elevated plasma homocysteine is a risk factor for arterosclerotic disease and is associated with increased severity of carotid-artery stenosis and peripheral arterial disease. In this study, we examine the precise relation of homocysteine to the number of coronary artery with stenosis.METHODS:One hundred and seventeen subjects who underwent coronary angiography from June to October 1998 in our hospital were recruited in this study. Cases (n = 101) with >or= 50% stenosis in at least one of the three coronary vessels were angiographically defined as having coronary heart disease (CHD). While subjects (n = 16) had 0% stenosis in all the three coronary vessels were considered as controls. CHD cases were divided into single-vessel (n = 29), double-vessel (n = 35) and triple-vessel group (n = 37). Plasma homocysteine was measured within 1 week before angiography in all subjects.RESULTS:Mean plasma homocysteine level was significantly higher in coronary patients than in controls [(17.56 +/- 1.14) micromol/L versus (10.59 +/- 0.43) micromol/L, P = 0.02]. Homocysteine level in the triple-vessel group or double-vessel group was significantly higher compared with that in the controls [(19.49 +/- 1.98) micromol/L versus (10.59 +/- 0.43) micromol/L, P = 0.006 and (17.41 +/- 2.03) micromol/L versus (10.59 +/- 0.43) micromol/L, P = 0.036, respectively]. The level of homocysteine in the stingle-vessel group tended to be slightly higher as compared with that in the controls [(15.2 +/- 61.18) micromol/L versus (10.59 +/- 0.43) micromol/L, P = 0.16].CONCLUSION:Homocysteine level is elevated in patients with coronary heart disease. Higher level of homocysteine is associated with increased number of coronary arteries with stenosis.
Zhonghua nei ke za zhi 1999
